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The -44 C/G (rs1800972) polymorphism of the ?-defensin 1 is associated with increased risk of developing type 2 diabetes mellitus.

ABSTRACT: BACKGROUND:The aim of this study was to establish the association of two polymorphisms of the ?-defensin 1 gene (DEFB1, OMIM#602056) with the risk of developing type 2 diabetes mellitus (T2DM) in a group of Mexican patients. METHODS:The 5'UTR -20 G/A, and -44 C/G polymorphisms of DEFB1 gene were genotyped by 5' exonuclease TaqMan assays in a group of 252 patients with T2DM and 522 healthy control. RESULTS:Under dominant and additive models adjusted for the risk factors, the C allele of the -44 C/G polymorphism was associated with increased risk of T2DM (OR = 1.63, 95% CI = 1.07-2.48, pCdom = 0.021 and OR = 1.42, 95% CI = 1.05-1.91, pCadd = 0.023, respectively). In addition, the linkage disequilibrium analysis showed that AC haplotype was associated with an increased risk of developing T2DM (OR = 4.39, p = 0.04). The in-silico analysis showed that the -44 C allele produces a binding site for the transcription factor Ikaros (IK). CONCLUSION:This study demonstrates that the C allele of -44 C/G polymorphism, as well as haplotype AC are associated with the presence of T2DM in the Mexican population. The variation in this polymorphism of the DEFB1 gene could increase the migration of the macrophages to pancreatic islets accelerate the ?-cell dysfunction in T2DM.

SUBMITTER: Martinez-Rios MA

PROVIDER: S-EPMC6382445 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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The -44 C/G (rs1800972) polymorphism of the β-defensin 1 is associated with increased risk of developing type 2 diabetes mellitus.

Martinez-Rios Marco Antonio MA Vargas-Alarcon Gilberto G Peña-Duque Marco Antonio MA Perez-Mendez Oscar O Rodriguez-Perez Jose Manuel JM Perez-Hernandez Nonanzit N Herrera-Maya Gabriel G Posadas-Sanchez Rosalinda R Posadas-Romero Carlos C Fragoso Jose Manuel JM

Molecular genetics & genomic medicine 20181213 1

<h4>Background</h4>The aim of this study was to establish the association of two polymorphisms of the β-defensin 1 gene (DEFB1, OMIM#602056) with the risk of developing type 2 diabetes mellitus (T2DM) in a group of Mexican patients.<h4>Methods</h4>The 5'UTR -20 G/A, and -44 C/G polymorphisms of DEFB1 gene were genotyped by 5' exonuclease TaqMan assays in a group of 252 patients with T2DM and 522 healthy control.<h4>Results</h4>Under dominant and additive models adjusted for the risk factors, the ...[more]

PMID: 30549243

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Project description:Introduction Periodontitis is a multifactorial disease caused by periodontopathic bacteria and influenced by both genetic and environmental factors. Genetic predispositions are found to play a crucial part in the onset and progression of periodontal disease. There is a two-way relationship between diabetes and periodontitis with severe periodontal tissue destruction seen in diabetic patients. Antimicrobial peptide, β-defensin-1 (DEFB1 gene), plays an important role in the innate immune responses and forms the first line of host defense against periodontal pathogens. Single nucleotide polymorphisms (SNPs) in the specific genetic loci of the DEFB1 gene and its expression level could confer a degree of risk or protection from periodontitis associated with diabetes. The present study determined the association between SNPs at the 5' untranslated region (UTR) in the DEFB1 gene and susceptibility to periodontitis associated with type 2 diabetes mellitus (T2DM) and analyzed the effect of 5' UTR polymorphisms on DEFB1 gene expression. Methods SNPs in the 5' UTR of the DEFB1 gene (-20G>A (rs11362), -44C>G (rs1800972), and -52G>A (rs1799946)) were genotyped by polymerase chain reaction (PCR) followed by Sanger sequencing. The study group included periodontitis (n = 40), periodontitis with T2DM (n = 20), and periodontally and systemically healthy as controls (n = 40). DEFB1 gene expression was determined by real-time PCR in the study group comprising periodontitis (n = 20), periodontitis with T2DM (n = 15), and healthy controls (n = 20). The effect of 5' UTR polymorphisms on the expression was analyzed by statistical tools. Results Statistically significant higher prevalence of the variant AA genotype of rs11362 was observed in periodontitis (odds ratio (OR) = 3.64, 95% confidence Interval (CI) = 1.16-11.43, p = 0.04) and periodontitis with T2DM (OR = 5.14, 95% CI = 1.29-20.5, p = 0.03) in comparison with healthy controls. Moreover, there was a significant increase of the variant AA genotype of rs1799946 in periodontitis (OR = 3.88, 95% CI = 1.19-12.68, p = 0.04) compared to healthy controls. DEFB1 gene expression was downregulated in periodontitis and upregulated in periodontitis with T2DM patients when compared to healthy controls but was not statistically significant. No significant association was found for the effect of SNPs of the DEFB1 gene on its expression. Conclusion From the SNP analysis, it can be inferred that the presence of SNPs at the 5' UTR (rs11362 and rs1799946) in the DEFB1 gene may be an important predictive factor for periodontitis.

Project description:IntroductionType 1 diabetes mellitus (T1DM) is characterized by autoimmune destruction of insulin-producing pancreatic beta (β-) cells. Previous studies suggested an imbalance between and pro- and anti-inflammatory cytokines exacerbates T1DM development.ObjectivesWe aimed to test the hypothesis that patients with T1DM carry a higher frequency of regulatory genes associated with low levels of the anti-inflammatory cytokines interleukin-4 (IL-4), its receptor (IL-4R), and interleukin-10 (IL-10).MethodsAccordingly, we compared frequencies of five different single nucleotide polymorphisms (SNPs) in T1DM patients and healthy controls who had been typed for HLA-DRB1, HLA-DQA1, and HLA-DQB1 genes.ResultsThe frequencies of rs2070874 (IL-4) alleles C and T differed between T1DM patients and controls (cp = 0.0065), as did their codominant (cp = 0.026) and recessive (cp = 0.015) models. Increased frequencies were observed in T1DM patients for HLA alleles: DRB1*03 (pc < 0.0013), DRB1*04 (cp = 0.0169), DQA1*03 (cp = 0.0222), DQA1*05 (cp < 0.0006), DQB1*02 (cp = 0.0005), and DQB1*06 (cp < 0.0005). And lower frequencies were observed for: DRB1*07 (cp = 0.0078), DRB1*11 (cp = 0.0013), DRB1*13 (cp < 0.0364), DRB1*15 (cp < 0.0013), DQA1*01 (cp < 0.0006), and DQA1*02 (cp = 0.0348). Certain DRB1: DQA1: DQB1 haplotypes showed greater frequencies, including, 03:05:02 (p < 0.0001) and 04:03:03 (p = 0.0017), whereas others showed lower frequencies, including, 07:02:02 (p = 0.0032), 11:05:03 (p = 0.0007), and 15:01:06 (p = 0.0002). Stratification for the above HLA haplotypes with rs2070874 C/C exhibited no significant differences between T1DM patients overall and controls. However, when stratified for the vulnerable HLA haplotype (03:05:02/04:03:03), young patients in whom T1DM began at ≤13 years had a higher frequency of the SNP (rs2070874 C/C); a gene associated with low IL-4 production (p < 0.024).ConclusionThis study suggests that possession of the rs2070874 C/C genotype, which is associated with low production of IL-4, increases the risk of T1DM in young individuals carrying vulnerable HLA alleles/haplotypes.

Dataset Information

The -44 C/G (rs1800972) polymorphism of the ?-defensin 1 is associated with increased risk of developing type 2 diabetes mellitus.

Publications

The -44 C/G (rs1800972) polymorphism of the β-defensin 1 is associated with increased risk of developing type 2 diabetes mellitus.

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